Project 4 will investigate integration of patient-specific data (acquired from anatomic and physiological imaging and clinical Studies before and during therapy) together with other data and models of tumor and normal tissue response into individualized adaptive plan optimization. Though delivering the dose distribution that was prescribed at the beginning of treatment has been the goal of modifications of standard radiation planning, it is likely that this goal is not the best overall objective for each patient, when one takes into account the additional clinical and other information which can become available during the course of therapy. That is, each patient, and their tumor, changes over the course of treatment. However, approaches to deal with these changes have been makeshift and focused, in isolation, on only one issue at a time. The sum of those single-step corrections is vety unlikely to achieve the overall best solution for the patient. Therefore, the overall goal of this project is to develop and study methods that will integrate important clinical, imaging, and biological data and changes into an overall planning strategy to optimize each patient's treatment course in order to truly individualize therapy. Thus, this project addresses needed research on utilizing imaging and clinical response factors for decision support, adaptive treatment strategies and plan optimization. In particular, Specific Aim 1 will be tasked with organizing the expanse of population and patient specific data that exists and applying that information to provide knowledge-based decision support to help facilitate the best adaptive course of patient treatment. Specific Aim 2 will design and investigate the adaptive treatment strategies that will lead to the greatest therapeutic gain for individual patients. The goal of Specific Aim 3 is to provide the radiation therapy treatment plan or set of plans that epitomizes the recommended course of therapy for each patient. Adaptive clinical trial strategies for the treatment sites studied in Projects 1 and 2 will be formulated; and we will run simulations to test these strategies for a variety of scenarios. Uncertainty assessments determined in Project 3 will also be incorporated. As part of the adaptive strategies will depend on planning quality, optimization studies will continue towards improving the quality and ease of achieving the best plans that take advantage of improved knowledge with regard to individual patient responses.